Composition comprising salt of 1, 1&#39;-methylene-bis-(2-hydroxy-3-naphthoic acid) and 1-diphenylmethyl-4-methyl-piperazine



United States Patent COMPOSITION COMPRISENG SALT OF LldadETiYLENE-BES-(Z-HYDROXY-SNAPHTHOIC AGED) AND 1-DiPHENYLh lETHYL-i-METHYL-PLERA= ZiNE Emanuel Kroll and Herbert A. Lieberman, Dover, Del,assignors to International Latex Corporation, Eover, Del, a corporationof Delaware No Drawing. Filed Apr. 20, 1961, ar. No. 104,245

5 Claims. (Cl. MST-o5) This invention is tasteless salts of cyclizine,l-diphenyl- 4-methylpiperazine.

Cyclizine is effective in combating motion sickness and in its usualforms is readily soluble in the fluids of the mouth and stomach. Evenvery slight solubility in the mouth causes its extremely bitter taste tobe exhibited while ready solubility in the stomach is desirable to giveit quick drug action. The compound and its usual salts, however, are soottensively bitter that they have to be made into tablets designed to beswallowed whole. Many people are not able to conveniently swallow Wholetablets and therefore cannot protect themselves against motion sicknesswith cyclizine unless they chew the tablets. The bitterness of the drugis so pronounced that few people care to chew the tablets and thereforethe benefits of this drug cannot be enjoyed by all. The unpleasant tasteis shown not only by the base form of the drug but also by all itsheretofore known compounds such as the hydrochloride,cyclohexylsulfamate, tartrate, etc.

The present inventors have found that the revolting bitterness of thiscompound may be eliminated or reduced practically to zero by reacting itwith l,1'-methylene-bis- (Z-hydroxy-B-naphthoic acid), otherwise knownas pamoic acid, to form salts which are palatable because they are soinsoluble in the month they do not exhibit any bitterness. While this isan important advance, the cyclizine parnoate salts take so long todissolve in the stomach that their efiicacy is less than desired. Theinventors have unexpectedly found that they can increase the solubilityof the cyclizine pamoate salts in the stomach without affecting theirinsolubility in the mouth. By this invention the cyclizine drug remainstasteless in the mouth but fast acting in the stomach and it is thuspossible for the first time to administer cyclizine in a tasteless formhaving a quick drug action comparable to that obtained from theobjectionable, bitter form of the drug.

These desirable results are obtained by first converting the cyclizineto insoluble cyclizine pamoate and then com bining it with a suitablesurfactant to selectively increase its solubility in aqueous acidsolutions. Many difierent types of surfactants will serve the purpose,but not all. The surfactant chosen should be miscible or soluble inaqueous acid solutions; be compatible with the cyclizine pamoate salt inthat it should not react with it to form salts which are physiologicallyinert or insoluble in dilute hydrochloric acid; be non-toxic andtasteless in the quantities used; and be capable of reducing the surfacetension of aqueous 0.1 N hydrochloric acid. Surfactants which reduce thesurface tension below 70 dynes per centimeter are operative; those whichreduce the surface tension below 50 dynes per centimeter constitute apreferred group, and those which reduce the surface tension below 35dynes per centimeter give optimum results. As used in this specificationtasteless means that for most people there is no taste whatever or solittle taste as to be completely unobjectionable.

Pamoic acid has two carboxyl groups which may participate in thesalt-forming reaction with cyclizine. One mol equivalent of parnoic acidwill react with one mol equivalent of cyclizine .to give a monocyclizinecompound Where one carboxyl group only of the pamoic acid has icereacted. By using two mols of cyclizine for one mol of pamoic acid, adouble cyclizine compound is obtained Where both carboxyl groups havereacted. The salt where two mols of cyclizine have reacted with one molof pamoic acid has a higher concentration of cyclizine and may be moreadvantageous than the mono-cyclizine salt in certain situations. Boththe monoand di-cyclizine pamoate salts, however, are free frombitterness and are efiective in motion sickness. The reaction betweenthe two components may be carried out in various ways. Salts containingone mol of cyclizine and one mol of pamoic acid may be prepared byreacting the monopotasslum salt of pamoic acid with one mol of cyclizinehydrochloride in an aqueous solution or other suitable solvent mediumincludes mixtures of solvents. By using the dipota-ssium salt of pamoicacid and two mols of cyclizine hydrochloride, a double cyclizine salt ofpamoic acid is obtainable. The two components may also be reacted bytreating the free acid with the free cyclizine base in a suitablesolvent such as methanol, isopropanol, or N,N-dimethyltormam-ide andprecipitating the product with a nonsolvent such as water it necessary.Other reaction media may be chosen from solvents which are neutral andpolar such as the alkanols, etc. The reaction to form the desired saltoccurs as soon as the ingredients are mixed but heat is effective inensuring completeness of the reaction.

EXAMPLE 1 3.88 gm. of pamoic acid, 0.01 mol, were suspended in 200 ml.of methanol. 5.65 gm. of cyclizine base, 0.02 mol, were added and themixture warmed to approximately 60 C. for A2 hour, the resultingprecipitate of 4.7 gm. (102% of theory) being collected on a filter. Theprecipitate was thoroughly washed with hot methyl alcohol and then driedovernight at 60 C. Tasteless dicyclizine salt of pamoic acid melting at168-17l C. was obtained.

EXAMPLE 2 3.88 gm. or 0.01 mol of pamoic acid Were suspended in 200 ml.of methyl alcohol, To this suspension was added 6.05 gm. or 0.02 mol ofcyclizine hydrochloride and the whole warmed as in Example 1. 1.12 gm.or 0.02 mols of KOH dissolved in 10 ml. of water were then added withadditional heating. The resulting precipitate of 4.4 gms. was washedwith hot methanol and then with water, after which it was driedovernight at 60 C. The dicycliz-ine salt of pa-rnoi'c acid was tastelessand had a melting point range as in Example 1.

EXAMPLE 3 8.52 gm. or 0.02 mol of monopotassium pamoate were allowed toreact with 8.04 gm. or 0.02. mol of cyclizine hydrochloride in 300 ml.of methanol. The precipitated reaction product of 12.3 gm. was collectedon a Buchner tunnel, washed with methanol and dried overnight at 60 C.The monocycliz-ine salt melted at 211212 C.

EXAMPLE 4 Suspend homogeneously 430 grams or about 1.0 mol of finelypowdered l,l'-methy1ene-bis-(Z-hydroxy 3 naphthoic acid) in 6000 ml. ofmethyl alcohol. Dissolve 309.5 grams or 1.1 mob of cyclizine base in2000 ml. of methyl alcohol and add to the pamoic acid mixture withconstant stirring. Mix well for at least one hour. Collect theprecipitate in a Buchner funnel and wash oil the excess cyclizine basewith about 3000 m1. of methyl alcohol. Dry overnight at 45 C. in oven.Yield is 705 grams, 97.3% of theory, of the monocyclizine salt of1,1-meth ylene-bis-(2-hydroxy-3-naphthoic acid) having a melting pointof 208209 C. Other solvents in which the reactants are at leastpartially soluble and which do not enter into the reaction may be used.

The cyclizine pamoate salts are generally tasteless greenish-yellowpowders insoluble in water or alcohol but soluble in hydrochloric acid.They may be made as a suspension in flavored syrups for administrationin liquid doses or dispensed in any pharmaceutically acceptable carrier.They may be made into chewable tablets or incorporated in lozenges,lollypops, chewing gum, etc. by methods known in the art.

Surfactants having the characteristics enumerated earlier herein andsuitable for the purpose of this invention fall into many chemicalclassifications. They may be cationic, anionic, amphoteric or non-ionic.Included for example are alkyl sulfonates such as octylsulfonate anddodecyl sulfonate; quaternary ammonum compounds such as cetyl dimethylbenzyl ammonium chloride and the alkyl trimethyl ammonium chlorides soldby Armour as Arquads; alkyl aryl sulfonates such as dodecyl benzenesulfonate and sodium ethyl naphthalene sulfonate; fatty acid esters ofhydroxy compounds, exemplified by glycerin, sorbitol and sugars,including esters such as sorbitol oleate and polyglyceryl oleate;alkylene oxide surfactants; alkyl benzene alkali metal sulfates such asisopropyl benzene sodium sulfonate and dodecyl benzene sodium sulfonate;di(n-octyl) sulfosuccinic acid, its salts and esters; fatty alcoholsulfates such as sodium lauryl sulfate, and the like. It is to beunderstood that the examples are illustrative only since any surfactanthaving the specified characteristics will work.

Particularly useful are polyalkylene oxide ethers obtained by condensingalkylene oxides such as ethylene oxide, propylene oxide, glycide and thelike with organic compounds having at least one active hydrogen atom,for example at least one carboxyl, hydroxyl, amino, or amido group, etc.The amount of alkylene oxide condensed with the organic compound used inthe preparation of the particular surfactant is not critical so long assuflicient alkylene oxide is used to make the surfactant miscible orsoluble in water and aqueous acid solutions. This class of surfactantsmay be represented by the general formula where R represents the residueof an organic carboxy, hydroxy, amino or amido compound, etc. containingan active hydrogen, R and R represent hydrogen or a lower alkyl and n isan integer. Surfactants of this type are well known in the art andinclude, among others, those disclosed in U.S. Patents 1,970,578;2,085,706; and 2,213,477.

Examples of suitable organic compounds are acids such as caproic,capryllic, capric, lauric, myristic, palmitic, oleic, linoleic,ricinoleic, stearic, dihydroxy stearic, eleostearic, erucic, behenicacid and the like; hydroxy compounds as hexyl, octyl, decyl, dodecyl,tetradecyl, octadecyl, cetyl, oleyl alcohols and diethylene glycol,octodecanediol, octomethyl glycol, decamethyl glycol, gycerine,propylene glycol, butylene glycol, mannitol, mannitan, sorbitol,sorbtian and the like. Esters containing an active hydrogen such asesters of the above acids with alcohols may also be used, includingmonoglycerides and diglycerides and partial esters of hexahydricalcohols such as the mono and poly fatty acid esters of sorbitol andmannitol, etc. disclosed in U.S. Patents 2,322,820 and 2,322,821,Phenols shown in U.S. 2,213,477 are additional examples of usefulhydroxy compounds. Amino compounds are hexyl, octyl, decyl, dodecyl,tetradecyl, octadecyl, cetyl, oleyl amine, etc. Arnides include hexyl,octyl, decyl, dodecyl, tetradecyl, octadecyl, cetyl, oleyl amide and thelike. Suitable also are the compounds disclosed in U.S. 2,674,619 wherethe organic compound containing an active hydrogen is first condensedwith propylene oxide and then reacted with ethylene oxide to form thefinal surfactant.

Specific examples of these alkylene oxide surfactants which may be usedinclude polyoxyethylene stearate (Atlas Powders Myrj 45) polyoxyethylenepalmitate, polyoxyethylene ester of coco fatty acids (Armours EthofatC-), polyoxyethylene oleate, polyoxyethylene lauryl ether (Atlas Brijand polyoxyethylene oleyl ether (Atlas Brij 30 and 35) polyoxyethyleneoleyl ether (Atlas G3920), polyoxyethylene glyceryl ether,polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylenesorbitan monopalmitate (Tween polyoxyethylene sorbitan tristearate(Tween polyoxyethylene sorbitan trioleate (Tween polyoxyethylenesorbitan monostearate (Tween 60), polyoxyethylene sorbitan monooleate(Tween 80), polyoxyethylene ether of isooctyl phenol, polyoxyethyleneether of butylphenol, polyoxyethylene ether of octadecyl phenol,polyoxyethylene ether of hexyl amine, polyoxyethylene ether of octylamine, polyoxyethylene ether of coco amine, polyoxyethylene ether ofsoybean amine, polyoxyethylene ether of stearyl amine (ArmoursEthomeen), polyoxyethylene ether of stearamide, poly oxyethylene etherof oleyl amide (Armours Ethomid 0/15), polyoxyethylene ether ofhydrogenated tallow amide (Armours Ethomid HT/60) polyoxyethylene etherof coco amine (Armours Ethomeen C-20), polyoxyethylene ether ofpolyoxyproylene (Wyandottes Pluronics F-68), polyoxyethylene ether ofdodecyl alcohol, polyoxyethylene ether of diethylene glycol,polyoxyethylene ether of glycerol monooleate, polyoxypropylene ether ofisooctyl phenol, and polyglycidyl ether of isododecylphenol.

The amount of undersurfactant depends upon the particular surfactantused. With some surfactants a quantity as low as 0.1% by weight based onthe weight or volume of the dosage form containing the cyclizine pamoatehas been found sufiicient, whereas with others as much as 0.5% or moremay be required. The surfactant chosen should not have any unpleasanttaste of its own in the concentration used and should be soluble ormiscible in aqueous acid solutions. The end result is that an effectivequantity reduces the time needed for the cyclizine pamoate salts todissolve in acid media without materially influencing theirtastlessness.

Representative examples illustrating the present invention are shown inthe following table where an acidic aqueous solution corresponding tothe acidity of synthetic gastric juice U.S.P., was prepared and thecyclizine salt, with and without the surfactant, was stirred into ml. ofthe acid solution at a constant rate. The time needed for solution wasnoted.

TAB LE I Salt Surfactant Amount, Minutes Cyclizine HOL MonoeyclizineParnoete.

Myrj 45. Tween 20. Tween 40- Tween 60 Tween 65 Tween 80. Tween 85.Pluronie F- Brij30 Brij 35 Ethofat 0/25 Ethomeen C/ZO. do 01101242 PNPPFQQPPPFPQP mencncnenovcnenmoiencxm Dicyelizino Pamoate.

Myrj 45 Tween 60 Tween 65.

1 Equivalent to 100 mg. cyclizine HCl. Ethylene glycol bis(aminoethylether) tetraaeetic acid.

The following examples are illustrative of palatable formulationscontaining the products of this invention and are not to be construed aslimiting.

Water, qs. to make 100.00 gm.

The cyclizine pamoate is suspended in about 20 ml. water. The sucrose isdissolved in sufficient water to make a syrup and the surface activeagent, syrup, glycerin, saccharin sodium and sorbic acid are all thenadded to the pamoate suspension and mixed well. The suspending agent,Kelgin LV, which has been wetted in a separate container with some ofthe water, is then added, followed by the addition of the coloring agentand the flavor. Sufficient water is then added to make the total volumeof 100 m1.

EXAMPLE 6 Cyclizz'ne pamoate suspension Cyclizine monopamoate gm 1.10Guar gum gm .60 Sucrose gm 34.00 Glycerin ml 10.00 Sorbic acid em .05Saccharin sodium gm .10 Tween 60 gm .50 Colors, qs.

Flavors, qs.

Water, qs. to make 100.00 gm.

A procedure similar to that of Example is used.

EXAMPLE 7 Cyclizine pamoate suspension Grams Cyclizine monopamoate 1.10

- Karayagum .50

Methylparaben .05

Saccharin sodium .10

Myrj 51 .50 Flavor qs. Water, qs. to make 100.00 ml.

A procedure similar to that of Example 5 is used. The monocyclizinepamoate of the above examples may be substituted by 0.77 gm. ofdicyclizine pamoate.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compositions shown and describedherein as modifications and equivalents may be made within the teachingof our invention, and the invention is therefore to be limited only bythe scope of the appended claims.

We claim: 7

1. A pharmaceutical composition comprising the salt of1,1-methylene-bis-(2-hydroxy-3-naphthoic acid) and 1-diphenylmethyl-4-methylpiperazine and a non toxic tasteless surfactantwhich reduces the surface tension of aqueous 0.1 N hydrochloric acidbelow dynes per centimeter and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to claim 1 wherein thesurfactant is polyalkylene oxide ether.

3. A composition as defined in claim 2 wherein the polyalkylene oxidesurfactant is polyoxyethylene stearate.

4. A composition as defined in claim 2 wherein the polyoxyethylene oxidesurfactant is polyoxyethylene sorbitan monolaurate.

5. A composition as defined in claim 2 wherein the polyalkylene oxidesurfactant is polyoxyethylene lauryl ether.

References Cited by the Exner UNITED STATES PATENTS 2,630,435 3/53Baltzly et al 260-268 2,647,121 7/53 Jacoby 260-268 2,667,493 1/ 54Slack 260-313 2,834,782 5/58 Schlesinger et a1 260-268 2,890,985 6/59Marsh et a1. 167-65 2,925,417 2/60 Worth et al 260-240 2,976,213 3/61Murphey 167-65 FOREIGN PATENTS 154 12/52 Phillipines.

' OTHER REFERENCES Chinn et al.: Journal Investigative Dermatology, vol.20, pp. 177-84 (1953).

Chun: J. of Pharm. Science, vol. 50, No. 9, pp. 732-736, 1961, presentedat A. Ph. A. Meeting, 1960.

Cooper, J. Am. Pharm. Assoc., Science Ed., vol. 46, No. 9, pp. 520-524,1957.

Fuhrmann: Chem. Abst., vol. 50, pp. 6653-6654, 1956.

Jowdy: Carolina I. of Pharmacy, vol. 33, p. 465, 1952.

McCutcheon: Soap and Chemical Specialities, vol. 34,

,No. 2, p. 62, February 1958.

Nakamura: Chem. Abst, v01. 53, p. 4661, 1959.

Steck: J. Am. Pharm. Assoc., vol. 41, 1952, p. 455.

Wilson: American Drug Index, 1961, p. 430.

LEWIS GOTTS, Primary Examiner.

IRVINGNIARCUS, M. O. WOLK, Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,188,273 June 8, l9

Emanuel Kroll et a1.

It is hereby certified that error appears in the above numbered pat entrequiring correction and that the said Letters Patent should read ascorrected below.

Column 2, line 30, for "5.65 gm." read 5.64 gm. column 4, line 4, strikeout "ether (Atlas Brij 30 and 3S) polyoxyethylene oleyl; line 23, forpo1yoxyproylene" read polyoxypropylene same column 4, line 29, for"undersurfactant" read surfactant Signed and sealed this 30th day ofNovember 1965.

(SEAL) Allest:

ERNEST W. SWIDER EDWARD J. BRENNER Atteating Officer Commissioner ofPatents

1. A PHARMACEUTICAL COMPOSITION COMPRISING THE SALT OF1,1''-METHYLENE-BIS-(2-HYDROXY-3-NAPHTHOIC ACID) AND1DIPHENYLMETHYL-4-METHYLPIPERAZINE AND A NON TOXIC TASTELESS SURFACTANTWHICH REDUCES THE SURFACE TENSION OF AQUEOUS 0.1 N HYDROCHLORIC ACIDBELOW 70 DYNES PER CENTIMETER AND A PHARMACEUTICALLY ACCEPTABLE CARRIER.